Faiyaz-Ul-Haque Muhammad, Al-Sayed Moeenaldeen D, Faqeih Eissa, Jamil Masood, Saeed Anjum, Amoudi Mohamed Saleh, Kaya Namik, Abalkhail Halah, Al-Abdullatif Ahmed, Rashed Mohamed, Al-Owain Mohammed, Peltekova Iskra, Zaidi Syed H E
Dr. Muhammad Faiyaz-Ul-Haque, Department of Pathology,, College of Medicine,, King Khaled University Hospital,, King Saud University, T: 966-11-4699377, F: +966-11-4672462,
Ann Saudi Med. 2014 Mar-Apr;34(2):107-14. doi: 10.5144/0256-4947.2014.107.
L-2-hydroxyglutaric aciduria is a neurometabolic disorder with autosomal recessive mode of inheritance in which patients exhibit elevated L-2-hydroxyglutaric acid in body fluids, central nervous system manifestations, and increased risk of brain tumor formation. Mutations in L2HGDH gene have been described in L-2-hydroxyglutaric aciduria patients of different ethnicities. The present study was conducted to perform a detailed clinical, imaging and genetic analysis.
A cross-sectional clinical genetic study of 16 L-2-hydroxyglutaric aciduria patients from 4 Arab consanguineous families examined at the metabolic clinic of the hospital.
Genomic DNA was isolated from the blood of 12 patients and 10 unaffected family members, and the L2HGDH gene was sequenced. DNA sequences were compared to the L2HGDH reference sequence from GenBank.
All patients exhibit characteristic clinical, biochemical, and imaging features of L-2-hydroxyglutaric aciduria, and 4 patients exhibited increased incidence of brain tumors. The sequencing of the L2HGDH gene revealed the c.1015delA, c.1319C > A, and c.169G > A mutations in these patients. These mutations encode for the p.Arg339AspfsX351, p.Ser440Tyr, and p.Gly57Arg changes in the L2HGDH protein, respectively. The c.169G > A mutation, which was shown to have a common origin in Italian and Portuguese patients, was also discovered in Arab patients. Finding of the homozygous c.159T SNP associated with the c.169G > A mutation in Arab patients points to an independent origin of this mutation in Arab population.
The detailed description of clinical manifestations and L2HGDH mutation in this study is useful for diagnosis of L-2-hydroxyglutaric aciduria in Arab patients. While reoccurrence of an L2HGDH mutation in L-2-hydroxyglutaric aciduria patients of different ethnicity is extremely rare, the c.169G mutation has an independent origin in Arab patients. It is likely that this mutation may also be present in patients of other ethnicities.
L-2-羟基戊二酸尿症是一种常染色体隐性遗传的神经代谢紊乱疾病，患者体液中L-2-羟基戊二酸水平升高，有中枢神经系统表现，且患脑肿瘤风险增加。不同种族的L-2-羟基戊二酸尿症患者中均有L2HGDH基因突变的报道。本研究旨在进行详细的临床、影像学及遗传学分析。
对来自4个阿拉伯近亲家庭的16例L-2-羟基戊二酸尿症患者进行横断面临床遗传学研究，研究在医院代谢门诊进行。
从12例患者及10名未患病家庭成员的血液中提取基因组DNA，对L2HGDH基因进行测序。将DNA序列与GenBank中的L2HGDH参考序列进行比较。
所有患者均表现出L-2-羟基戊二酸尿症的典型临床、生化及影像学特征，4例患者脑肿瘤发病率增加。L2HGDH基因测序显示这些患者存在c.1015delA、c.1319C>A和c.169G>A突变。这些突变分别导致L2HGDH蛋白发生p.Arg339AspfsX351、p.Ser440Tyr和p.Gly57Arg改变。在意大利和葡萄牙患者中发现的具有共同起源的c.169G>A突变，在阿拉伯患者中也被发现。在阿拉伯患者中发现与c.169G>A突变相关的纯合c.159T SNP，表明该突变在阿拉伯人群中有独立起源。
本研究对临床表现及L2HGDH突变的详细描述有助于阿拉伯患者L-2-羟基戊二酸尿症的诊断。虽然不同种族的L-2-羟基戊二酸尿症患者中L2HGDH突变的再次出现极为罕见，但c.169G突变在阿拉伯患者中有独立起源。该突变可能也存在于其他种族的患者中。
